General anesthetics and therapeutic gases

A. Hall and M. Leuwer

10

General anesthetics and therapeutic gases

Immunologic The incidence of hypersensi­ tivity reactions during anesthesia has been underestimated, because clinical symptoms vary and the diagnosis is often not obvious. The incidence of allergic reactions during anesthesia has been estimated in a systema­ tic follow-up of patients for 2 years (70 000 anesthetics) (1C). When a hypersensitivity reaction was suspected or when there were unexplained adverse reactions during anesthesia, blood was sampled to measure histamine and tryptase and skin tests were performed 4–6 weeks later. Of the 39 patients enrolled, 8 were excluded because of lack of skin tests, 22 had clinical features compatible with immediate hypersensitivity reactions and 9 had reactions rated as ‘unex­ plained’ by the attending physician. After systematic investigation, 22 hypersensitivity reactions were detected (15 patients with obvious and 7 with unexplained reactions) during anesthesia. This increases the esti­ mated incidence of hypersensitivity reactions from 1:4667 to 1:3180 anesthetics. Tryptase concentrations were increased in only 50% of these patients, and the positive and nega­ tive predictive values of tryptase for a diag­ nosis of anaphylaxis were 100 and 60% respectively. Latex was the major causative agent, followed by neuromuscular blocking agents and antibiotics.

Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32010-1 � 2010 Elsevier B.V. All rights reserved.

ANESTHETIC VAPORS (SEDA-27, 119; SEDA-29, 129; SEDA-30, 137; SEDA-31, 217) HALOGENATED VAPORS Gastrointestinal The incidence of post­ operative nausea and vomiting (PONV) after lumbar disc surgery has been investi­ gated in a prospective non-randomized cohort study in 625 patients who sequen­ tially received isoflurane, desflurane, and sevoflurane in an O2/air mix depending on the year of surgery (2c). They all received two antiemetics (metoclopramide and dexamethasone). The rates of PONV were similar with all three volatile anesthetics (i­ soflurane 9.3%, desflurane 11%, and sevo­ flurane 11%). Multiple logistic regression identified well-known independent risk factors for PONV, such as female sex, non­ smoking, a history of PONV and duration of anesthesia.

Desflurane (SED-15, 1072; SEDA-30, 137; SEDA-31, 217) Cardiovascular Desflurane 6% prolonged the QT interval to over 440 ms until 30 min­ utes after the end of inhalational anesthesia in 20 children undergoing inguinal hernia repair, all of whom had a normal preoperative electrocardiogram (3c). Sevo­ flurane 2% had no effect. Ear, nose, throat In 19 boys, mean age 7 years, middle ear pressure was measured in

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both ears at baseline, after 5, 10, and 15 minutes of desflurane administration and 10 minutes after withdrawal (4C). There was a significantly increased middle ear pres­ sure, even at 5 minutes, which peaked at 15 minutes and remained significantly raised at 10 minutes after withdrawal of desflurane. The authors thought that this might cause problems, such as tympanic rupture, displacement of tympanic mem­ brane grafts, hemotympanum or varying degrees of hearing loss.

Liver Hepatotoxicity has been ascribed to desflurane (5A).
A 15-month-old boy with Mo¨ bius syndrome (congenital oculofacial paralysis), who had had two previous uneventful general anes­ thetics with isoflurane and remifentanil, under­ went an uneventful Nissen fundoplication using desflurane and remifentanil. On the first postoperative day he had an upper gastro­ intestinal bleed and was found to have a coagulopathy with raised liver enzymes. However, liver ultrasound was unremarkable. A diagnosis of exclusion of desflurane hepato­ toxicity was made.

Other potential causes for hepatotoxicity were ruled out. Desflurane (and isoflurane) produce low concentrations of a trifluoro­ acetylated product, and this can be enough to produce hepatotoxicity in the sensitized patient. However, hepatic trifluoroacetylated microsomal proteins could not be measured. In another case, desflurane-induced hepatitis was associated with hapten and autoantigen-specific IgG4 antibodies (6A).
A 22-year-old woman underwent uneventful exploratory laparotomy with general anesthe­ sia using desflurane. On day 17 she developed dark urine, pruritus and vomiting. On day 21 she developed jaundice and raised liver func­ tion tests, but normal liver ultrasonography. All viral screens were negative. She was tested for three antibodies known to be increased in volatile gas-associated hepatitis and was posi­ tive for all three (trifluoroacetyl-specific IgG4 (TFA IgG4) and 58 kDa endoplasmic reticulum protein and CYP2E1 autoantibodies).

The authors concluded that drug-induced liver injury may be an autoimmune response

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triggered by native hepatic proteins covalently linked to TFA IgG4. They identified sus­ ceptibility factors for drug-induced liver injury, including previous exposure, female sex, and a history of autoimmune disease.

Isoflurane

(SED-15, 1921; SEDA-30, 138; SEDA-31, 218) Drug withdrawal The effects of isoflurane withdrawal have been reported (7A).


An ex-premature infant girl, now 4 years old, developed status asthmaticus and was given isoflurane for bronchodilatation. After she had been weaned off other sedation, the isoflurane was also reduced. Each time severe bronchospasm occurred within a few hours of extubation, requiring rapid reintubation and subsequent tracheostomy, suggesting possible tolerance. After 20 continuous days of inhaled therapy (end tidal concentration up to 2%), she developed choreoathetoid movements on dosage reduction, precipitating bronchospasm. She was given a ‘weakening’ dose of cisatra­ curium (0.04 mg/kg/hour) to facilitate dosage reduction. After 18 days, the isoflurane was weaned and then subsequently the cisatracur­ ium. One year later there were no motor or new cognitive defects or abnormal movements.

Methoxyflurane (SED-15, 2290) Observational studies Methoxyflurane, which had fallen out of favor because of potential nephrotoxicity, has started to be used again for procedural and pre-hospital sedation in emergencies. Its use has been studied in adults and in children. In a prospective, non-randomized obser­ vational case series of 83 adults paramedics gave methoxyflurane via a hand-held pen­ throx inhaler delivering 0.2–0.4% (dilutor hole open) and 0.5–0.7% (hole closed) (8c). There was a statistically significant reduction in pain scores after 5 minutes with only minor adverse effects in 19%. The adverse effects included nausea (n = 7), euphoria (n = 3), dizziness (n = 2), and one each of headache, hallucinations, sore throat, and lip paresthesia. Ramsay sedation scores

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showed a mean of 2, and only one patient became significantly drowsy (Ramsay score 5). There was a moderately high level of satisfaction with the drug among the para­ medics (82%) and patients (72%). Methoxyflurane has also been studied in a prospective, observational case series of 14 children aged 6–13 years (9c). It was deliv­ ered using the hand-held penthrox inhaler, delivering 0.1–0.2% (with dilutor hole open) and 0.3–0.4% (dilutor hole closed). There were no major adverse events. However, five patients had minor adverse events, including agitation, euphoria, blurred vision, and dizziness, and two had cough, both of whom had the dilutor hole closed to increase the concentration of methoxyflurane.

Sevoflurane

(SED-15, 3123; SEDA-29, 129; SEDA-30, 138; SEDA-31, 218)

Cardiovascular In 54 patients the Tp-e (the time interval between the peak and the end of the T wave, a measure of transmural dispersion of repolarization), which is a more sensitive indicator of the risk of torsade de pointes than QT interval, was measured (10c). The patients were randomized to sevoflurane 1, 1.25 or 1.5 age-adjusted minimum alveolar concentration (MAC) after induction with 8% sevoflurane. There was a significant increase in QTc duration in all the groups compared with pre-induction. However, there were no significant increases in Tp-e after sevoflurane exposure, suggesting that sevoflurane has a low potential for causing torsade de pointes. The increase in QTc interval could be explained by the high dose of sevoflurane that was given at induction. Nervous system The epileptiform effects of sevoflurane have been studied under four different conditions, including tidal and vital capacity induction, 2 and 4% end tidal mini­ mal alveolar concentration and inclusion of hyperventilation in 40 patients (11c). There were epileptiform discharges in 12 patients, but there were no differences between the groups. These discharges were not associated with hemodynamic changes. Post hoc

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univariate analysis showed that female sex, increased dose of sevoflurane, and speed of onset of induction were statistically signifi­ cant susceptibility factors for epileptiform discharges. Emergence agitation after sevoflurane has been reported when propofol 1 mg/kg was added before the end of the procedure in two placebo-controlled studies in chil­ dren aged 2–7 years undergoing either MRI scanning (12C) or strabismus surgery (13C). In the first study there was a signifi­ cant reduction in emergence agitation (27% versus 4.8%) with the addition of propofol and no increase in adverse effects; time to eye opening and recovery room discharge were not different. In the second study there were also significant reductions in emergence agitation, but the time to removal of the laryngeal mask and emer­ gence time were significantly longer after propofol. There were no major adverse events or respiratory compromise and recovery room discharge times were equiva­ lent, suggesting that longer emergence times may not be clinically significant. Neuromuscular function The effects of sevoflurane 0, 1.7 and 3.4% on neuromuscular function have been studied in patients with myasthenia gravis undergoing anesthesia without neuromuscular blockade in a singlecenter cohort study (14c). T1 and the T4/T1 ratio were measured by electromyographic sti­ mulation of the ulnar nerve. Three groups were identified: a control group and two groups of patients with myasthenia gravis, those who initially displayed fade and those who did not. In all three groups, increasing concentrations of sevoflurane reduced the T4/T1 ratio but more significantly in the patients with myasthe­ nia gravis who displayed fade, thus implying that the effect of sevoflurane could be pre­ dicted in these patients and further negating the need for neuromuscular blockade. Liver The repeated use of sevoflurane has been associated with fatal hepatic failure (15A).
A 69-year-old man with chronic renal insufficiency secondary to diabetes underwent general anesthesia with sevoflurane to repair a

246 subclavian artery after damage from an intravenous catheter. The procedure was uneventful but during the 20th postoperative hour he developed deep jaundice, abnormal liver function and a coagulopathy. Thoracotomy for suspected bleeding was negative. His clinical condition deteriorated rapidly, and he developed multiorgan failure with severe cerebral edema. He died on the 8th postoperative day. At post-mortem examination the liver was reduced in size, with multiple necrotic areas. Microscopic examination showed perivenular necrosis and intracellular calcium deposits.

The post-mortem findings were consis­ tent with previous studies that have proposed that hepatic damage may be due to disruption of intracellular calcium homeostasis, resulting in hepatic necrosis and a large amount of calcium deposition in hepatocellular cytoplasm. Musculoskeletal Malignant hyperthermia has again been reported in the case of a 7-year-old boy with three previous normal general anesthetics who underwent sevo­ flurane anesthesia without muscle relaxa­ tion for tympanoplasty (16A). Despite other classic signs of malignant hyperther­ mia (tachycardia and hyperthermia), there were no signs of muscle rigidity or masseter spasm and the rise in PECO2 was minor (4.8–5.2 kPa). Subsequent investigation showed that his father was susceptible to malignant hyperthermia but his mother was negative. Susceptibility factors Diseases Death occur­ red after volatile anesthesia in an infant w­ ith undiagnosed Duchenne muscular dystrophy (17A).
An 8-month-old ex-premature boy who had previously undergone eight general anesthetics with volatile agents died 12 hours after closure of an ileostomy with hyperthermia and rhabdomyolysis. Perioperatively he had a per­ sistent tachycardia and hypercapnea un­ responsive to treatment. Postoperatively, he developed a fever, increased serum creatinine and a coagulopathy. He became hypotensive and required inotropic support. Echocardio­ graphy showed poorly contracting ventricles. Despite optimum therapy, he deteriorated and died. At post-mortem examination there were dilated renal tubules and raised serum

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creatinine kinase and lactate dehydrogenase activities (21 093 and 21 393 IU respectively). Immunohistochemical staining showed un­ diagnosed Duchenne muscular dystrophy.

Trichloroethylene (SED-15, 3488; SEDA-29, 130; SEDA-30, 140; SEDA-31, 219) Nervous system A link between trichloro­ ethylene, parkinsonism and mitochondrial neurotoxicity has been postulated (18cE). In a questionnaire study of 134 previous empl­ oyees of a factory in which trichloroethylene had been used, 65 responded. They were equally spread between those who reported no symptoms of parkinsonism, 1–2 symptoms or 3 or more. The authors further evaluated the symptomatic and very symptomatic groups, of whom about 60% consented to undergo neurological testing. Both groups had significantly slower movements than age-matched controls. The asymptomatic patients also had slower fine motor hand movements than those of the age-matched controls, albeit faster than those of the symptomatic patients. In a parallel study, rats that were exposed to trichloroethylene for 6 weeks had significantly inhibited mitochondrial function in the substantia nigra. Drug overdose There have been two case reports of trichloroethylene overdose, one fatal, secondary to abuse, and one non-fatal after an industrial accident.
A 27-year-old man, a known thinner addict, developed chest and abdominal pain and drow­ siness. Imaging and blood investigations were normal apart from a respiratory alkalosis (19A). After 24 hours he developed increased liver enzymes (alanine transaminase 4920 IU/l and aspartate transaminase 9370 IU/l) and thrombo­ cytopenia (17  109/l). His liver enzymes continued to deteriorate and he developed dis­ seminated intravascular coagulation and a metabolic acidosis. All viral markers were nega­ tive. He was treated with respiratory and invasive hepatic support. His urinary trichloro­ acetate concentration was 24 mg/l (normally undetected). He subsequently developed renal insufficiency and cerebral edema. Electro­ encephalography showed flat waves and further brainstem testing confirmed the absence of brainstem reflexes. He died on the same day.

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Although no liver biopsy was performed, the very high AsT/AlT ratio suggested cen­ trilobular liver damage, which is the histo­ logical finding that has been found in animal studies and previous autopsy reports after poisoning with trichloroethylene. Severe hepatotoxicity with trichloroethylene alone is rare in humans and the patient may there­ fore have been exposed to other hepato­ toxic substances, such as alcohol.
A 54-year-old man was found unconscious beside a metal-degreasing machine in which trichloroethylene was used as a solvent. His serum trichloroethylene concentration was 9 mg/l and rapidly fell over the first 24 hours (20A). The urinary trichloroethylene concentration exhibited two peaks at 7 and 14 hours. Excretion of total urinary protein and enzymes (glutamine synthetase and N-acetyl-
-D-glucosaminidase) coincided with urinary excretion of trichloroethylene. Plasma urea and creatinine remained stable and he recovered completely.

Based on the blood concentration of tri­ chloroethylene and its urinary excretion, the exposure level was around 150 ppm (three times higher than statutorily recom­ mended). Glutamine synthetase is a mito­ chondrial enzyme that is found in a variety of tissues, including the kidneys, and speci­ fically the S3 segment of the proximal tubule. Excretion of this protein in the urine is early indication of damage to this segment and a high excretion rate relates to necrosis. N-acetyl-
-D-glucosaminidase is a lysosomal enzyme, also segmentally located in the S3 segment of the proximal tubule. This report, therefore, suggests a link between trichloroethylene poisoning and dysfunction of a specific segment of the proximal tubule, segment S3.

OTHER VAPORS Nitrous oxide (SED-15, 2550; SEDA-29, 131; SEDA-30, 140; SEDA-31, 221) Metabolism Nitrous oxide (N2O) interferes with methionine synthesis via the oxidation of vitamin B12, causing bone marrow and

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nervous system changes. Reversible myelo­ neuropathy with previously undiagnosed per­ nicious anemia and a normal mean erythrocyte volume has been reported (21A).
A 27-year-old otherwise fit and well woman developed ascending numbness and bilateral lower-extremity weakness developing over 2–3 months starting 3 months after nitrous oxide-based anesthesia for dental procedures. She had normal cognition, cranial nerves and upper limb and proximal lower strength, but light touch sensation was reduced in the arms and over the trunk. Her gait was widened and ataxic. Myeloneuropathy was diagnosed. She had a mild anemia (hemoglobin 11.9 g/dl) with an mean cell volume (MCV) of 86 fl, serum B12 290 pg/ml, homocysteine 17 mmol/l, and positive antibodies to intrinsic factor. Nerve conduction studies showed an axonal sensory and motor polyneuropathy. Needle electromyography showed 2þ fibrillation and positive sharp waves with normal motor unit action potentials. An MRI scan of the cervical spine showed patchy enhancement in the posterior regions. She improved with a 10-month course of intra­ muscular vitamin B12 100 micrograms/month.

Hematological parameters have been measured in 95 female theatre nurses who had been exposed to anesthetic gases in oper­ ating theatres for 5–26 years and 90 control nurses who worked elsewhere in the same hospital. Initial hemoglobin, mean cell hemo­ globin (MCH), mean cell volume (MCV), and mean corpuscular hemoglobin concen­ tration (MCHC) were normal in both groups (22c). Despite these normal hematological parameters, vitamin B12 concentrations were lower and homocysteine concentrations significantly higher in the exposed group. In nurses who worked in theatres that exceeded the quoted US and German government guidelines for anesthetic gas concentrations, vitamin B12 concentrations were statistically significantly lower and homocysteine con­ centrations significantly higher than those in nurses who worked in theatres where expo­ sure was within the guidelines. There was also a significant negative correlation between theater nitrous oxide concentrations and vitamin B12 concentrations and a significant positive correlation between theater nitrous oxide concentrations and homocysteine, but no correlation with duration of exposure to nitrous oxide. Hyperhomocysteinemia at

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these concentrations is an independent risk factor for cardiovascular disease and this may warrant further investigation.

Xenon Gastrointestinal Xenon is emetogenic. In a prospective, randomized trial in 142 patie­ nts who received either xenon anesthesia or propofol total intravenous anesthesia, the xenon group had statistically significantly greater incidences of nausea and vomiting both in the recovery area and in the first 24 hours, despite having received similar amounts of cumulative opioids; late nausea and vomiting did not differ between the groups (23c). As propofol has antiemetic properties (24C), its use may have mitigated the emetogenic effect of xenon found in this study. A comparison of xenon with another anesthetic vapor in addition would be desirable.

INTRAVENOUS AGENTS: NON-BARBITURATE ANESTHETICS Etomidate

(SED-15, 1302; SEDA-30, 140; SEDA-31, 221)

Cardiovascular Complete atrioventricular blockade after etomidate has been reported (25A).
A 71-year-old woman was given atropine and etomidate 17 mg for electroconvulsive therapy (ECT), having undergone a full course uneventfully in the previous year. She devel­ oped complete heart block with an atrial rate of 100/minute and an intrinsic ventricular rate of 10/minute, which resolved spontaneously after 30 seconds. On three occasions she had had asymptomatic bradycardia (20/minute) after induction with etomidate 18 mg and sux­ amethonium 50 mg, which had been attributed to suxamethonium. On this occasion suxa­ methonium was not given and treatment was abandoned. Subsequent investigation showed no abnormalities and the event was attributed to etomidate.

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Etomidate is suspended in 35% propy­ lene glycol, which has been shown to cause atrioventricular dissociation in animals and rarely in humans (26E). It is possible that this may have been the causative agent rather than the etomidate itself.

Nervous system Transient myoclonus is a reported adverse effect of etomidate, but a case report has suggested that it can cause more prolonged myoclonus (27A).
A healthy 69-year-old man with treatmentrefractory depression, who had previously received etomidate for ECT, was again given etomidate 10 mg and developed severe sus­ tained myoclonus lasting 10 minutes. His vital signs were stable and oxygenation was easily maintained via a facemask. Anesthesia was s­ uccessfully induced 45 minutes later with 1% propofol.

Etomidate-induced myoclonus has been studied in a double-blind, placebo-con­ trolled trial of the benefit of pre-treatment with low-dose midazolam in 40 patients undergoing elective cardioversion for atrial fibrillation after cardiac surgery (28c). In those who were given placebo the incidence of myoclonus was 50%; it was mild in six patients, moderate in three, and severe in one. After pre-treatment with midazolam 0.015 mg/kg, only two patients out of 20 had mild myoclonus. Although etomidate is a proconvulsant and prolongs the duration of seizures during ECT, seizures are rare. Two cases have been reported (29c).
A 49-year-old white man was given etomidate 20 mg and suxamethonium 120 mg uneventfully for ECT. Before a second course he was given the same dose of etomidate and had a general­ ized tonic–clonic seizure, which lasted 450 sec­ onds and ended spontaneously, associated with bradycardia, which responded to glycopyrro­ late. Electroencephalography was consistent with childhood benign occipital lobe epilepsy. On the next occasion he was given the same dose of etomidate and had a generalized tonic–clonic seizure. It lasted 450 seconds and ended spontaneously, but was associated with glycopyrrolate-responsive bradycardia. Electro­ encephalography was consistent with childhood benign occipital lobe epilepsy.

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A 38-year-old African woman with a schizoaffective disorder had been treated successfully with ECT. On each previous occasion, she had developed mild myoclonus after being given etomidate; however, on this occasion, after eto­ midate 18 mg the myoclonus developed into seizure activity. Bifrontal electroencephalogra­ phy showed possible epileptiform waves. The seizure activity resolved spontaneously after 4 minutes. Later electroencephalography showed no epileptiform activity.

The authors suggested that in patients at increased risk of etomidate-induced sei­ zures, propofol should be considered for induction of anesthesia.

Adrenal suppression from etomidate In a prospective, unblinded, randomized, controlled trial, adults with trauma were ran­ domized into two groups who received either etomidate 0.3 mg/kg (n = 18) or fentanyl 100 micrograms þ midazolam 5 mg (n = 12), both with suxamethonium 1 mg/kg (30c). Baseline and 6-hour serum cortisol were measured and an ACTH stimulation test was performed at 4–6 hours. Baseline serum cortisol was the same in the two groups (310 and 270 µg/l), but after 4–6 hours etomidate reduced serum cortisol (180 µg/l versus 280 µg/l). After the ACTH stimulation test, those who had received etomidate had a sig­ nificantly lower rise in cortisol (42 µg/l versus 112 µg/l), suggesting impaired adrenal func­ tion. Despite having the similar severity of injuries, those who received etomidate required significantly more units of red blood cells and fresh frozen plasma; they also had an increased duration of both ICU and hospital stay and an increased number of ventilator days. This study had many lim­ itations: it was small and unpowered and about 50% of the patients were withdrawn for a number of reasons, including problems with consent. This may have skewed the results, as 11 of the 31 patients who were withdrawn received etomidate. There was also a difference in blood and clotting products between the two groups. However, it is not clear why the authors felt that it could be accounted for by

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‘physiologic alterations’ between the two groups. Resuscitation of the patients was at the discretion of the attending physician, and perhaps this also had an influence. A prospective non-randomized observa­ tional study investigated 40 critically ill adults without septic shock who required intubation for respiratory distress, all had etomidate and suxamethonium for induction. Serial serum cortisol and 11
-deoxycortisol concentra­ tions were taken at baseline and 60 minutes after corticotrophin stimulation tests per­ formed at 12, 24, 48, and 72 hours (31c); 80% of the patients fulfilled previously pub­ lished criteria for adrenal insufficiency (32c) at 12 hours and 46% at 24 hours. This fell to 9% and 7% at 48 and 72 hours respec­ tively. A subgroup analysis showed that the patients with adrenal insufficiency required significantly more noradrenaline support (1.8 mg/hour versus 0.2 mg/hour). The lack of a control group does not allow complete confidence in suggesting that it was etomi­ date rather than the pathology that caused the adrenal suppression. Also, patients who died within 12 hours were excluded, which may also have skewed the data. However, this study presents some evidence for a more prolonged period of adrenal insuffi­ ciency after the administration of a single dose of etomidate. The effects of propofol and etomidate have been compared in patients with severe aortic stenosis undergoing aortic valve repair in a double-blind, randomized study of 66 patients (33c). Hypotension was significantly more likely in those who received propofol (20/30 versus 8/30), although the range of doses of propofol to achieve a bispectral index of 60 was large (40–400 mg), which may have influenced vasopressor require­ ments. Pulmonary capillary wedge pressure, cardiac index, systemic vascular resistance index and stroke volume fell in both groups to a similar extent. More of those who were given propofol required phenylephrine at the time of induction, but those who required the drug in the two groups received the same dose. Cortisol concentrations were com­ parable preoperatively and on the first postoperative morning. Immediately post­ operatively those who were given etomidate

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had significantly lower serum cortisol con­ centrations (250 nmol/l versus 700 nmol/l). There was an inverse relation between the dose of etomidate and the total cortisol con­ centration. Cortisol stimulation tests were not performed. There were no differences in out­ come, length of stay and mortality, although the sample size was only powered to detect reductions in blood pressure and may have been too small to identify differences in mortality. Adrenal insufficiency after a single dose of etomidate has been reported (34A).
A 74-year-old woman who underwent an uncomplicated abdominoperineal resection was induced with etomidate and suxametho­ nium and 6 hours postoperatively became leth­ argic, bradycardic and hypotensive. She did not respond to atropine and fluids. Transcutaneous pacing was initiated, and she improved hemo­ dynamically. Subsequently a temporary transvenous pacing wire was inserted. A random cortisol was 176 µg/l (although the temporal relation to the dose of etomidate was unclear). She was given intravenous hydrocortisone 100 mg tds and 6 hours after the first steroid dose did not need further pacing.

The authors concluded that adrenal insuf­ ficiency should be considered in patients with postoperative shock who have received etomidate who do not respond to fluids and vasopressors.

Acid–base balance Hyperosmolar, increased anion-gap metabolic acidosis and associated hyperglycemia have been reported after infusion of etomidate in propylene glycol (35A).
A 33-year-old woman with a large subarachnoid hemorrhage and poorly controlled intracranial pressure (ICP) was given etomidate by infusion following failure of pentobarbital to control ICP. She also received intravenous dexamethasone 20 mg 12 hourly. Twenty-four hours after the start of the infusion she became markedly acidotic (pH 7.06, anion gap 23 mmol/l), hyperglycemic (36 mmol/l) and hyperosmolar (serum osmolarity 422 mOsm/l). Urinary ket­ ones were absent. Despite treatment, her meta­ bolic derangement returned to normal only when the etomidate infusion was stopped, after a total dose of 2800 mg in 508 g of propylene glycol.

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Propylene glycol is 45% excreted unchanged by the kidneys and the rest is metabolized by hepatic alcohol dehydro­ genase to pyruvate, lactate and acetate. Thus, in hepatic and renal impairment, propylene glycol toxicity can cause hyperosmolar acidosis with hyperglycemia from increased gluconeogenesis. Dexametha­ sone may also have contributed to the hyperglycemia by increasing insulin resis­ tance, although it was continued after withdrawal of etomidate and after her blood glucose normalized (36r).

Ketamine Observational studies The addition of ketamine to propofol is thought to counteract the cardiorespiratory depression that occurs when propofol is used alone, whereas propo­ fol is thought to reduce the psychometric and emetic effects of ketamine. In a prospective case series of 114 patients of all ages, a mix­ ture of propofol 10 mg/ml þ ketamine 10 mg/ ml (‘ketofol’) was used for procedural seda­ tion in an emergency department (37c). There was no standardization of the preprocedural analgesia used, and a large proportion (42/114) received intravenous or oral opioids. Only three patients required additional propofol to complete the proce­ dure. Eight had minor adverse events, includ­ ing three airway malalignments requiring manipulation, two emergence reactions, and one case of self-limiting atrial fibrillation. Four had major adverse events, including three patients with apnea and/or hypoxia requiring airway adjuncts and 100% oxygen, one of whom was acutely intoxicated and one had received narcotics. Comparative studies The effects of mida­ zolam on ketamine-induced emergence reactions have been investigated in 100 chil­ dren undergoing adenotonsillectomy (38c). All were given intramuscular ketamine 7 mg/kg and atropine 0.015 mg/kg and half were given midazolam 0.1 mg/kg. There were no severe adverse events in either group. In the immediate postoperative period, mild

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reactions were similar, but moderate reactions were less common in those who received midazolam (3.6% versus 25%). On day 1, mild reactions were frequent in both groups. On day 2, 71% of the children who received ketamine without midazolam had mild reactions, whereas 75% of those who received midazolam group had no emergence reactions. The incidence of immediate PONV (at 0–4 hours) was significantly reduced by midazolam, but this was reversed in the period up to 24 hours, when those who received midazolam had a higher incidence of vomiting. This may have been attributable to the relative half-lives of the drugs. Nervous system In a randomized, placebo-controlled study, 60 children aged 3–7 years had ketamine 0.5 mg/kg in 2 ml or placebo infiltrated into the tonsillar fossa after day case adenotonsillectomy (39c). Using the childrens’ hospital of eastern ontario pain score (CHEOPS), 26/30 in the ketamine group versus 3/30 in the placebo group had no pain in the immediate postoperative period. The time to first requirement for analgesia was significantly longer in those who received ketamine and the dose required was lower. There were no hallucinations or negative behaviors and the incidence of nausea and vomiting was the same in the two groups. There were no delayed discharges. Respiratory Prolonged apnea has been reported after the use of ketamine (40A).
An 11-month-old, 7-kg full-term girl was given intramuscular ketamine 35 mg and glycopyrrolate 0.05 mg before elective plas­ tic surgery. She started to have ineffective respirations, followed by apnea requiring intubation. There was no laryngospasm or excessive secretions. Spontaneous respiration resumed after 90 minutes. There were no complications.

Respiratory depression has been noted before with high doses of intramuscular ketamine (10 mg/kg), or when it is co­ administered with other sedatives, or in neonates with electrolyte abnormalities.

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However, it is unusual with a low dose in an otherwise healthy subject.

Psychiatric The influence of adding an infusion of ketamine 0.1 mg/kg/hour to tramadol 0.2 mg/kg/hour has been assessed in a double-blind, randomized, placebocontrolled trial in 120 adults undergoing elective laparotomy (41C). Ketamine produced superior analgesia, with 54% less morphine consumption than in the placebo group. There were no differences in nausea and antiemetic drug use, psychomotor performance, sleep disturbance, or nondisturbing hallucinations. However, three patients withdrew from the study because of disturbing hallucinations; all had received ketamine. In a randomized, double-blind, placebocontrolled trial, 73 adults with trauma and severe acute pain (as defined by a visual analogue scale) received ketamine 0.2 mg/ kg or placebo (isotonic saline) in addition to morphine 0.1 mg/kg followed by 3 mg every 3 minutes. Ketamine significantly reduced morphine consumption (0.20 mg/kg versus 0.15 mg/kg), despite no differences in pain scores between the groups (42C). There were more adverse effects with ketamine, with an increased incidence of neuropsychia­ tric effects (hallucinations, dizziness, diplopia, and dysphoria). No patient required treat­ ment for these adverse effects and patient satisfaction was the same in the two groups. The investigation period was very short (30 minutes), and this may have skewed the identification of adverse effects, although the study was not powered to look at this. Gastrointestinal The addition of intra­ venous low-dose ketamine (2.5 micro­ grams/kg/minute) to a standard patientcontrolled morphine infusion has been stu­ died in 42 patients after elective bowel resection (43c). The mean time to passing flatus or stools, return of bowel sounds, or drinking without vomiting was the same in the two groups. There were significantly more adverse effects in those who were given ketamine, 32% of whom had

252

hallucinations, perhaps because benzodia­ zepines were not used. There were no dif­ ferences between the groups with respect to nausea and nightmares. All the patients who had hallucinations wanted to remain in the study, as they thought that they were getting the active drug.

Urinary tract Patients with a history of recreational ketamine abuse commonly have urinary symptoms. The index case in a series of nine presented with a 6-month history of painful hematuria, dysuria, urgency, and post-micturition pain after taking daily ketamine (44A). Urinalysis, cultures, and cytology were normal. An abdominal CT scan showed a very small capacity bladder with marked inflammatory changes, and a biopsy showed chronic ulcerative cystitis with eosinophil infiltration. Antibiotics and glucocorticoids were ineffective, and the symptoms were partly controlled by withdrawal of ketamine. Another eight cases presented in a similar fashion, and if symptoms did not resolve completely with ketamine withdrawal, pentosan polysulphate (to supplement the glycosaminoglycan layer of the bladder) was effective. The mechanism of ketamine­ induced ulcerative cystitis is unclear. However, there were high concentrations of norketamine and hydroxynorketamine in the urine of recreational users, and these metabolites may cause bladder irritation. In four bladder biopsies there was a degree of eosinophil infiltration, which is considered the final common pathway for allergic cystitis mediated by IgE-activating mast cells.

Propofol

(SED-15, 2945; SEDA-29, 132; SEDA-30, 142; SEDA-31, 222)

Cardiovascular A mixture of propofol 1 mg/kg þ fentanyl 1 microgram/kg has been compared with spinal anesthesia with hyperbaric lidocaine 10 mg in american society of anesthesiologists (ASA) I and

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ASA II patients undergoing prostate biopsy (45c). Those who received propofol þ fen­ tanyl had significantly more hypotension a­ nd required increased boluses of ephedrine. Propofol and xenon have been compared in ASA III and ASA IV patients under­ going non-elective cardiac surgery (46c). Those who received propofol had lower mean arterial pressure after induction and poorer myocardial performance index and circumferential fiber shortening, suggesting impaired left ventricular function. However, xenon was associated with a significant increase in the rate of PONV. There have been contradictory results in studies of whether propofol has any effect on cardiac conduction (47A).
A 49-year-old woman with a history of palpitations had a third molar extracted under propofol sedation and local anesthesia with lidocaine. Her preoperative electrocar­ diogram was normal, but shortly afterwards a delta wave appeared and persisted after injection of 2% plain lidocaine. She was hemodynamically stable, so surgery continued. She was given 2% lidocaine 3.6 ml with 1:80 000 adrenaline and 10 minutes later the delta wave resolved and she regained sinus rhythm. A postoperative electrocardiogram was normal.

This may have been due to reduced sympa­ thetic tone, sinus node automaticity, and atrial refractoriness. Systemic absorption of adrenaline may have shortened conduction in the atrioventricular node and accessory pathways, causing the delta wave to disappear. The oculocardiac reflex is a common pro­ blem during strabismus surgery, causing bradycardia and even asystole on manipula­ tion of the eye. The effect of intravenous anesthetics has been investigated in a dou­ ble-blind, randomized comparison of 120 children aged 3–9 years who were allocated to propofol 3 mg/kg or ketamine 1 or 2 mg/kg for induction. Ketamine significantly reduced the incidence of the oculocardiac reflex from 14/40 (placebo) to 4/40 (1 mg) and 1/40 (2 mg); it also significantly reduced the amount of rescue opioid analgesia required postoperatively (48c).

General anesthetics and therapeutic gases

Chapter 10

Respiratory In 82 patients who underwent sedation with propofol for mainly minor orthopedic procedures, the mean starvation time was 5.5 hours and the mean initial dose was 0.5 mg/kg in those with and without complications (49c). There were 28 sedation events in 17 people. Hypoventilation was the commonest and nine developed brief hypox­ emia (mean 1.2 minutes, SpO2 < 90%); none required assisted ventilation. All the episodes resolved with simple airway adjust­ ments and supplementary oxygen. There were similar results in a larger retrospective audit of children undergoing radiotherapy for 3833 oncology procedures (50c). There were 49 complications (1.3%), of which one was hemodynamic instability; the others were airway complications, none of which required advanced airway interven­ tion. There were no episodes of laryngo­ spasm. Univariate analysis showed that the use of adjuncts (benzodiazepines, opioids, and ketamine) was significantly associated with an increased risk of complications. This has been reinforced by a report of aspiration pneumonitis in a patient who had eaten before the operation and received a large dose of propofol and opiates (51A).
A 65-year-old woman needed reduction of an ankle fracture 5 hours after a large meal taken with alcohol. She received fentanyl 100 micrograms followed by 20–40 mg boluses of propofol (total 120 mg). Fracture reduction was unsuccessful. 20 minutes later she developed wheezing but had a normal chest X-ray. An hour later she was given further fentanyl 100 micrograms and propofol 60 mg and she vomited and aspirated. She became hypoxic and hypotensive and required intuba­ tion. There were patchy areas bilaterally on the chest X-ray. Recovery was uneventful.

In a prospective case series of procedural sedations in 404 starved and non-starved patients in an emergency department, the attending physician gave opiates in 63% of cases (52c). There were respiratory adverse effects in 22% after a mean bolus dose of propofol 0.82 mg/kg and a total dose of 1.78 mg/kg. All responded to basic airway manoeuvres and there were no cases of aspira­ tion, intubation, or unplanned admissions. A smaller non-randomized study in 37 patients also showed no major adverse

253

effects (apnea, desaturation, airway com­ promise, or hypotension) after the use of propofol 0.5–1 mg/kg for sedation in the emergency department (53A). Again, most patients received variable amounts of opi­ ate analgesia. In a crossover study of children who received sedation for lumbar puncture with propofol 2 mg/kg plus either alfentanil 20 micrograms/kg or ketamine 1 mg/kg, those who were given alfentanil had a statis­ tically significant increase in respiratory depression, resulting in reduced oxygen saturation. However, advanced airway manoeuvres were not required (54c). There were no other differences between the groups. Nervous system Propofol withdrawal seizures have been reported (55A).
A 51-year-old woman received propofol 150 mg followed by an infusion of 6.5 mg/kg/ hour for 90 minutes for a metatarsal bone graft. She also received fentanyl 100 micrograms and lidocaine 10 mg. During recovery she had tonic–clonic movements and was unresponsive for 3 minutes; she was treated with lorazepam. A second event occurred and further loraze­ pam and phenytoin were given. Afterwards she was post-ictal and had no recall of the events. Blood tests and electroencephalography were unremarkable postoperatively, except for a raised serum prolactin concentration.

Although propofol is usually described as being anticonvulsant (56c), there have been reports of seizure-like events after its administration. This description of a seizure-like event with a subsequent rise in prolactin may have indicated true seizure activity. A link between propofol and an antimuscarinic syndrome has been implied in a case report (57A).
A 20-year-old healthy man became drunk, fell, and dislocated his elbow. He received therapeutic doses of pethidine and prometha­ zine several hours before reduction of the dislocation and was given bolus injections of propofol (total 160 mg over 5 minutes); 5 minutes after the last dose of propofol he be­ came agitated and confused and required midazolam. Mydriasis was absent but the

254 antimuscarinic syndrome was diagnosed and he was given physostigmine 1 mg four times, with almost immediate effect. A drug screen was positive for caffeine, cannabinoids, nico­ tine, and the administered drugs and their metabolites.

This man received several drugs that have antimuscarinic activity (pethidine, pro­ methazine, and propofol), and the addition of alcohol may have further impaired choli­ nergic transmission. Sleep disturbance has been reported after propofol/remifentanil compared with sevo­ flurane anesthesia in 39 infants undergoing cleft lip/palate surgery (58c). Sleep patterns in both groups were disturbed in the 2 weeks after surgery compared with pre­ operatively. With propofol, sleep duration was significantly shorter than with sevoflur­ ane but awakening and inconsolable episodes were similar.

Psychological In 19 patients who under­ went colonoscopy or gastroscopy, took validated psychological tests, and answered driving licence questions to assess their ability to drive after anesthesia. Propofol caused significantly impaired memory imm­ ediately after anesthesia (59c). Four subjects had scores compatible with medium organic disorder and six had scores compatible with a slight disorder. After 1 hour, 91% and after 2 hours 94% had either no or slight memory deficits, implying rapid recovery.

Acid–base balance Prolonged infusion of propofol at high doses has been associated with the propofol infusion syndrome, a syn­ drome associated with unexplained metabolic acidosis, rhabdomyolysis and death (60c). Further cases have been reported (61A, 62A).
A 36-year-old white woman developed intract­ able epilepsy 2 weeks post-partum. Despite infusion of high-dose propofol (4.2 mg/kg/hour), her myoclonic jerks and electroencephalographic epileptiform activity continued. The dose of propofol was increased to 7.2 mg/kg/hour to achieve burst suppression for 19 hours, and then reduced to 4.8 mg/kg/hour. After a further 24 hours her urine became dark and serum

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triglyceride concentrations and creatine kinase activity were raised. She developed a fever and hypotension requiring inotropic support. Propo­ fol was withdrawn, but she developed acute renal insufficiency and required dialysis. Echocardio­ graphy showed global biventricular dysfunction without four-chamber dilatation and she pro­ gressed to bradycardia and eventually asystole. An autopsy showed normal cerebral hemi­ spheres with no ischemic changes. There was acute skeletal muscle aseptic necrosis, rhabdo­ myolysis and myoglobin casts in the renal tubules.
An 18-year-old man with a severe head injury after a high-speed road traffic accident was given an infusion of propofol 7.5 mg/kg/hour for more than 72 hours to control intracranial pressure. He developed dark urine and a rising creatine kinase, which peaked at 95 440 U/l, followed by acute renal insufficiency, a metabolic acidosis and cardiac arrest, from which he could not be resuscitated.
A 29-year-old woman with a severe head injury from a fall and an intracranial pressure of 28 mmHg was given high-dose propofol 4– 12 mg/kg/hour for 5 days. She subsequently underwent decompressive craniotomy for impending herniation and intraoperatively was found to be severely acidotic (pH 7.01, base excess –24 mmol/l, bicarbonate 7 mmol/l). Propofol was thought to be the culprit and anesthesia was switched to thiopental; over the next 5 hours the acidosis resolved, although on the next day she developed myoglobinuria with a rising creatine kinase (6966 U/l). She died the next day.

In a retrospective analysis of the case notes of 301 patients who underwent non­ invasive radiofrequency ablation for atrial dysrhythmias, 55 had had arterial blood gas measurements during the procedure. The controls were 267 patients undergoing carotid endarterectomy who had baseline arterial blood gas measurements. There was documented metabolic acidosis (defined as a base excess worse than –2 mmol/l) in 8.2% of the controls and 91% of those who received propofol. The authors did not report sodium, chloride, or bicarbonate concentrations, but they com­ mented that there was no relation between rate of fluid administration and the maximal negative base excess in these patients. The serious flaws of this work were outlined in a letter (63r). The definition of metabolic acidosis was at the lower limit of the normal range. Of the 301 patients who had arterial

General anesthetics and therapeutic gases

Chapter 10

blood gas measurements during radiofrequency ablation, 55 had poor respiratory status, making it impossible to interpret the metabolic picture. Furthermore, there was no temporal relation between propofol administration and the time of blood sam­ pling. Finally, the dose of propofol used was not high. It is therefore difficult to draw any conclusions from this study. The mechanism of propofol infusion syn­ drome is unknown. Some have described effects of high-dose propofol on mitochon­ dria, with changes in electron and calcium transport and oxidative phosphorylation. This suggests that the syndrome may be due to impaired fatty acid utilization in the mitochondria (61A). Others have shown dif­ fuse myonecrosis in both cardiac and skele­ tal muscle, suggesting susceptibility of muscle cells to the toxic effects of propofol because of high ATP requirements.

INTRAVENOUS AGENTS: BARBITURATE ANESTHETICS Thiopental sodium

(SED-15, 3395; SEDA-30, 146; SEDA-31, 226)

Respiratory The use of a laryngeal mask airway reduces pharyngeal discomfort and dysphonia compared with tracheal intuba­ tion. In a double-blind, randomized trial in 335 ASA I–III patients who received either propofol 2 mg/kg or thiopental 5 mg/kg without neuromuscular blockade, thiopental was associated with a greater incidence of sore throat at 2 and 12 hours (24% versus 13% and 15% versus 6% respectively) and more dysphagia at 2 hours (15% versus 3%) but no difference at 12 hours (64c). In those who required a second attempt at placement of a laryngeal mask airway, thiopental was associated with a significant increase in dysphagia (18% versus 9.5%). Thiopental caused more PONV (20% versus 11%). There was no difference in the use of supplementary analgesia,

255

although peri-operative analgesia was not mentioned. Patient satisfaction was the same in the two groups. Electrolyte balance Thiopental is com­ monly infused during neurocritical care to achieve burst suppression in patients in whom control of intracranial pressure is difficult. A rare complication of this appears to be imbalance in potassium regulation (65A).
A 32-year-old man with a large traumatic subarachnoid hemorrhage, an intraparenchy­ mal hematoma and hydrocephalus had raised intracranial pressure that was difficult to control. He was given thiopental 3  100 mg boluses a­ nd then 2.5 mg/kg/hour and subsequently 4 mg/ kg/hour. After 5 hours, his serum potassium concentration had fallen from 3.4 to 1.7 mmol/l. He was given potassium chloride 170 mmol over 14 hours, and 8 hours after the withdrawal of thiopental, the potassium had increased to 8.7 mmol/l. Renal function was normal.
A 53-year-old man with a left-sided subdural hematoma and midline shift developed a raised intracranial pressure (over 40 mmHg) and was given thiopental 5 mg/kg and then 3.75 mg/kg/hour. During 141 hours of coma, his serum potassium fell from 3.8 to 2.0 mmol/ l and he was given potassium chloride 600 mmol. Thiopental was withdrawn and the potassium rose to 8.5 mmol/l. There was mildly impaired renal function (serum creatinine 258 µmol/l).
A 24-year-old woman developed diffuse brain edema, a small posterior temporal contusion and raised intracranial pressure after a severe head injury. She was given thiopental 3 mg/kg followed by an infusion of 5 mg/kg/hour, which was reduced to 3 mg/kg/hour because of hemodynamic instability. A few hours later the serum potassium concentration fell from 3.7 to 2.8 mmol/l and she was given potassium chloride 330 mmol during the thiopental infusion. A few hours after the end of treatment, the potassium rose to 6.8 mmol/l associated with an unstable ventricular tachycardia, requiring DC cardioversion. Renal function was normal.

The implication of a fall in potassium concentrations without an increase in urinary excretion, and a sudden rise after withdrawal of thiopental in the absence of abnormal renal function, suggests a shift of potassium into the intracellular compart­ ment. Several hypotheses have been

256

suggested. One is inhibition of phospho­ fructokinase at high doses of thiopental, resulting in reduced lactate and pyruvate production, increasing intracellular pH and reducing potassium concentrations (66E). Second, inhibition of voltage-dependent neu­ ronal potassium channels can occur (67E). The use of catecholamines, insulin, and

Chapter 10

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mannitol in neurocritical care is common, and the reduction in potassium could there­ fore be multifactorial. Rebound hyperkale­ mia is less well described, and the authors suggested that rapid redistribution of the drug allows the concentrations of thiopental to fall rapidly, allowing redistribution of potassium to the extracellular environment.

References 1. Malinovsky JM, Decagny S, Wessel F, Guil­ loux L, Mertes PM. Systematic follow-up increases incidence of anaphylaxis during adverse reactions in anesthetized patients. Acta Anesth Scand 2008;52(2):175–81. 2. Wallenborn J,Rudolph C, Gelbrich G, Goer­ lich TM, Helm J, Olthoff D. The impact of isoflurane, desflurane, or sevoflurane on the frequency and severity of postoperative nau­ sea and vomiting after lumbar disc surgery. J Clin Anesth 2007;19(3):180–5. 3. Aypar E, Karagoz AH, Ozer S, Celiker A, Ocal T. The effects of sevoflurane and desflurane anesthesia on QTc interval and cardiac rhythm in children. Paediatr Anaesth 2007;17(6):563–7. 4. Ozturk O, Ilce Z, Demiraran Y, Iskender A, Guclu E, Yildizbas S. Effects of desflurane on middle ear pressure. Int J Pediatr Oto­ rhinolaryngol 2007;71(9):1439–41. 5. Cote G, Bouchard S. Hepatotoxicity after desflurane anesthesia in a 15-month-old child with Mobius syndrome after previous exposure to isoflurane. Anesthesiology 2007;107(5):843–5. 6. Anderson JS, Rose NR, Martin JL, Eger EI, Njoku DB. Desflurane hepatitis associated with hapten and autoantigen-specific IgG4 antibodies. Anesth Analg 2007;104(6):1452–3. Table of contents. 7. Cooper MK, Bateman ST. Cisatracurium in ‘weakening doses’ assists in weaning from sedation and withdrawal following extended use of inhaled isoflurane. Pediatr Crit Care Med 2007;8(1):58–60. 8. Buntine P, Thom O, Babl F, Bailey M, Ber­ nard S. Prehospital analgesia in adults using inhaled methoxyflurane. Emerg Med Australas 2007;19(6):509–14.

9. Babl F, Barnett P, Palmer G, Oakley E, Davidson A. A pilot study of inhaled methoxyflurane for procedural analgesia in children. Paediatr Anaesth 2007;17 (2):148–53. 10. Whyte SD, Sanatani S, Lim J, Booker PD. A comparison of the effect on dispersion of repolarization of age-adjusted MAC values of sevoflurane in children. Anesth Analg 2007;104(2):277–82. 11. Julliac B, Guehl D, Chopin F, Arne P, Burbaud P, Sztark F, Cros AM. Risk factors for the occurrence of electroencephalogram abnormalities during induction of anesthesia with sevoflurane in nonepileptic patients. Anesthesiology 2007;106(2):243–51. 12. Abu-Shahwan I. Effect of propofol on emer­ gence behavior in children after sevoflurane general anesthesia. Paediatr Anaesth 2008;18(1):55–9. 13. Aouad MT, Yazbeck-Karam VG, Nasr VG, El-Khatib MF, Kanazi GE, Bleik JH. A sin­ gle dose of propofol at the end of surgery for the prevention of emergence agitation in children undergoing strabismus surgery dur­ ing sevoflurane anesthesia. Anesthesiology 2007;107(5):733–8. 14. Nitahara K, Sugi Y, Higa K, Shono S, Hamada T. Neuromuscular effects of sevo­ flurane in myasthenia gravis patients. Br J Anaesth 2007;98(3):337–41. 15. Turillazzi E, D’Errico S, Neri M, Riezzo I, Fineschi V. A fatal case of fulminant hepatic necrosis following sevoflurane anesthesia. Toxicol Pathol 2007;35(6):840–5. 16. Bonciu M, de la Chapelle A, Delpech H, Depret T, Krivosic-Horber R, Aime MR. Minor increase of endtidal CO2 during

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sevoflurane-induced malignant hyperther­ mia. Paediatr Anaesth 2007;17(2):180–2. 17. Phadke A, Broadman LM, Brandom BW, Ozolek J, Davis PJ. Postoperative hyperther­ mia, rhabdomyolysis, critical temperature, and death in a former premature infant after his ninth general anesthetic. Anesth Analg 2007;105(4):977–80. 18. Gash DM, Rutland K, Hudson NL, Sullivan PG, Bing G, Cass WA, Pandya JD, Liu M, Choi DY, Hunter RL, Gerhardt GA, Smith CD, Slevin JT, Prince TS. Trichloroethylene: parkinsonism and complex 1 mitochondrial neurotoxicity. Ann Neurol 2008;63 (2):184–92. 19. Takaki A, Suzuki H, Iwasaki Y, Takigawa T, Ogino K, Matsuda H, Yagi T, Hanazaki M, Nakatsuka H, Katayama H, Matsumi M, Shoji B, Terada R, Kobashi H, Sakaguchi K. A 27-year-old man who died of acute liver failure probably due to trichloroethylene abuse. J Gastroenterol 2008;43(3):239–42. 20. Carrieri M, Magosso D, Piccoli P, Zanetti E, Trevisan A, Bartolucci GB. Acute, nonfatal intoxication with trichloroethylene. Arch Toxicol 2007;81(7):529–32. 21. Singer MA, Lazaridis C, Nations SP, Wolfe GI. Reversible nitrous oxide-induced myelo­ neuropathy with pernicious anemia: case report and literature review. Muscle Nerve 2008;37(1):125–9. 22. Krajewski W, Kucharska M, Pilacik B, Fob­ ker M, Stetkiewicz J, Nofer JR, WronskaNofer T. Impaired vitamin B12 metabolic status in healthcare workers occupationally exposed to nitrous oxide. Br J Anaesth 2007;99(6):812–8. 23. Coburn M, Kunitz O, Apfel CC, Hein M, Fries M, Rossaint R. Incidence of postoperative nausea and emetic episodes after xenon anesthesia compared with propofol-based anesthesia. Br J Anaesth 2008;100(6):787–91. 24. Apfel CC, Korttila K, Abdalla M, Kerger H, Turian A, Vedder I, Zernak C, Danner K, Jokela R, Pocock SJ, Trenkler S, Kredel M, Biedler A, Sessler DI, Roewer N: IMPACT Investigators. A factorial trial of six interven­ tions for the prevention of postoperative nausea and vomiting. N Engl J Med 2004;350(24):2441–51.

257

25. Combeer A. Complete atrioventricular block following etomidate. Eur J Anesthesiol 2007;24(12):1067–8. 26. Stowe DF, Bosnjak ZJ, Kampine JP. Com­ parison of etomidate, ketamine, midazolam, propofol, and thiopental on function and metabolism of isolated hearts. Anesth Analg 1992;74(4):547–58. 27. Kuczkowski KM, Hastings BH. Severe myoclo­ nus prior to electroconvulsive therapy following intravenous etomidate. AANA J 2007;75(2):88. 28. Huter L, Schreiber T, Gugel M, Schwarzkopf K. Low-dose intravenous midazolam reduces etomidate-induced myoclonus: a prospective, randomized study in patients undergoing elective cardioversion. Anesth Analg 2007;105(5):1298–302. Table of contents. 29. Griffeth BT, Mehra A. Etomidate and unpredicted seizures during electroconvul­ sive therapy. J ECT 2007;23(3):177–8. 30. Hildreth AN, Mejia VA, Maxwell RA, Smith PW, Dart BW, Barker DE. Adrenal suppres­ sion following a single dose of etomidate for rapid sequence induction: a prospective ran­ domized study. J Trauma 2008;65(3):573–9. 31. Vinclair M, Broux C, Faure P, Brun J, Genty C, Jacquot C, Chabre O, Payen JF. Duration of adrenal inhibition following a single dose of etomidate in critically ill patients. Inten­ sive Care Med 2008;34(4):714–9. 32. Annane D, Sebille V, Troche G, Raphael JC, Gajdos P, Bellissant E. A 3-level prognostic classification in septic shock based on corti­ sol levels and cortisol response to corticotro­ pin. J Am Med Assoc 2000;283(8):1038–45. 33. Bendel S, Ruokonen E, Polonen P, Uusaro A. Propofol causes more hypotension than etomidate in patients with severe aortic ste­ nosis: a double-blind, randomized study com­ paring propofol and etomidate. Acta Anesthesiol Scand 2007;51(3):284–9. 34. Lundy JB, Slane ML, Frizzi JD. Acute adre­ nal insufficiency after a single dose of etomi­ date. J Intensive Care Med 2007;22(2):111–7. 35. Ganesh A, Audu P. Hyperosmolar, increased-anion-gap metabolic acidosis and hyperglycemia after etomidate infusion. J Clin Anesth 2008;20(4):290–3. 36. Valladolid G, Varon J. Etomidate infusion: a cause of hyperglycemia? J Clin Anesth 2008;20(4):245–6.

258 37. Willman EV, Andolfatto G. A prospective evaluation of ‘ketofol’ (ketamine/propofol combination) for procedural sedation and analgesia in the emergency department. Ann Emerg Med 2007;49(1):23–30. 38. Erk G, Ornek D, Donmez NF, Taspinar V. The use of ketamine or ketamine–midazo­ lam for adenotonsillectomy. Int J Pediatr Otorhinolaryngol 2007;71(6):937–41. 39. Erhan OL, Goksu H, Alpay C, Bestas A. Ketamine in post-tonsillectomy pain. Int J Pediatr Otorhinolaryngol 2007;71(5):735–9. 40. Jonnavithula N, Kulkarni DK, Ramachan­ dran G. Prolonged apnea with intramuscular ketamine: a case report. Paediatr Anaesth 2008;18(4):330–1. 41. Webb AR, Skinner BS, Leong S, Kolawole H, Crofts T, Taverner M, Burn SJ. The addi­ tion of a small-dose ketamine infusion to tramadol for postoperative analgesia: a dou­ ble-blinded, placebo-controlled, randomized trial after abdominal surgery. Anesth Analg 2007;104(4):912–7. 42. Galinski M, Dolveck F, Combes X, Limoges V, Smaïl N, Pommier V, Templier F, Catineau J, Lapostolle F, Adnet F. Management of severe acute pain in emergency settings: ketamine reduces morphine consumption. Am J Emerg Med 2007;25(4): 385–90. 43. McKay WP, Donais P. Bowel function after bowel surgery: morphine with ketamine or pla­ cebo; a randomized controlled trial pilot study. Acta Anesthesiol Scand 2007;51(9): 1166–71. 44. Shahani R, Streutker C, Dickson B, Stewart RJ. Ketamine-associated ulcerative cystitis: a new clinical entity. Urology 2007;69(5):810–2. 45. Nishikawa K, Yoshida S, Shimodate Y, Igar­ ashi M, Namiki A. A comparison of spinal anesthesia with small-dose lidocaine and general anesthesia with fentanyl and propo­ fol for ambulatory prostate biopsy proce­ dures in elderly patients. J Clin Anesth 2007;19(1):25–9. 46. Baumert JH, Hein M, Hecker KE, Satlow S, Neef P, Rossaint R. Xenon or propofol anesthesia for patients at cardiovascular risk in non-cardiac surgery. Br J Anaesth 2008;100(5):605–11. 47. Wakita R, Takahashi M, Ohe C, Kohase H, Umino M. Occurrence of intermittent Wolff-Parkinson-White syndrome during intravenous sedation. J Clin Anesth 2008;20 (2):146–9.

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48. Choi SH, Lee SJ, Kim SH, Kim JH, Kwon HH, Shin YS, Lee KY. Single bolus of intra­ venous ketamine for anesthetic induction decreases oculocardiac reflex in children undergoing strabismus surgery. Acta Anesthesiol Scand 2007;51(6):759–62. 49. Weaver CS, Hauter WE, Brizendine EJ, Cordell WH. Emergency department proce­ dural sedation with propofol: is it safe? J Emerg Med 2007;33(4):355–61. 50. Anghelescu DL, Burgoyne LL, Liu W, Han­ kins GM, Cheng C, Beckham PA, Shearer J, Norris AL, Kun LE, Bikhazi GB. Safe anesthesia for radiotherapy in pediatric oncology: St. Jude Children’s Research Hos­ pital Experience, 2004–2006. Int J Radiat Oncol Biol Phys 2008;71(2):491–7. 51. Cheung KW, Watson ML, Field S, Campbell SG. Aspiration pneumonitis requiring intu­ bation after procedural sedation and analge­ sia: a case report. Ann Emerg Med 2007;49 (4):462–4. 52. Bell A, Treston G, McNabb C, Mony­ penny K, Cardwell R. Profiling adverse respiratory events and vomiting when using propofol for emergency department procedural sedation. Emerg Med Australas 2007;19(5):405–10. 53. Dunn T, Mossop D, Newton A, Gammon A. Propofol for procedural sedation in the emergency department. Emerg Med J 2007;24(7):459–61. 54. Crea F, Ruggiero A, Genovese O, Tortorolo L, Zorzi G, Chiaretti A. Safety and efficacy of two protocols for sedation in pediatric oncology procedures. Central Eur J Med 2008;3(1):77–82. 55. Zeiler SR, Kaplan PW. Propofol withdrawal seizures (or not). Seizure 2008;17(7):665–7. 56. Brown LA, Levin GM. Role of propofol in refractory status epilepticus. Ann Pharmaco­ ther 1998;32(10):1053–9. 57. Snow KA, Clements EA, Eppert AJ, Judge BS. Antimuscarinic syndrome after propofol administration in the emergency department. J Emerg Med 2007;33(1):29–32. 58. Steinmetz J, Holm-Knudsen R, Eriksen K, Marxen D, Rasmussen LS. Quality differ­ ences in postoperative sleep between propo­ fol-remifentanil and sevoflurane anesthesia in infants. Anesth Analg 2007;104(4):779–83. 59. Seidl S, Hausmann R, Neisser J, Janisch HD, Betz P. Severity and duration of mental

General anesthetics and therapeutic gases

60.

61.

62.

63.

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deficiency symptoms after intravenous administration of propofol. Int J Legal Med 2007;121(4):281–5. Cravens GT, Packer DL, Johnson ME. Inci­ dence of propofol infusion syndrome during noninvasive radiofrequency ablation for atrial flutter or fibrillation. Anesthesiology 2007;106(6):1134–8. Zarovnaya EL, Jobst BC, Harris BT. Propo­ fol-associated fatal myocardial failure and rhabdomyolysis in an adult with status epi­ lepticus. Epilepsia 2007;48(5):1002–6. Rosen DJ, Nicoara A, Koshy N, Wedder­ burn RV. Too much of a good thing? Tracing the history of the propofol infusion syn­ drome. J Trauma 2007;63(2):443–7. Rozet I, Lam AM. Propofol infusion syn­ drome or probable overinterpretation syn­ drome? Anesthesiology 2008;108(2):330. Author reply 331–2.

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64. Chia YY, Lee SW, Liu K. Propofol causes less postoperative pharyngeal morbidity than thiopental after the use of a laryngeal mask airway. Anesth Analg 2008;106 (1):123–6. 65. Bouchard PM, Frenette AJ, Williamson DR, Perreault MM. Thiopental-associated dys­ kalemia in severe head trauma. J Trauma 2008;64(3):838–42. 66. Nordstrom CH, Messeter K, Sundbarg G, Schalen W, Werner M, Ryding E. Cerebral blood flow, vasoreactivity, and oxygen con­ sumption during barbiturate therapy in severe traumatic brain lesions. J Neurosurg 1988;68(3):424–31. 67. Friederich P, Urban BW. Interaction of intravenous anesthetics with human neuro­ nal potassium currents in relation to clinical concentrations. Anesthesiology 1999;91 (6):1853–60.